This application is a competitive continuation of the grant "Pemphigus and Pemphigoid" seeking support for studies on the immunopathology of these diseases. Projects accomplished in the previous funding period include the following: In Pemphigus Vulgaris (PV) and Pemphigus Foliaceus (PF), a) we have fully defined the animal models of PV and PF. Using these models we have demonstrated the minimal role of b) plasminogen activator and c) complement activation in the pathogenesis of acantholysis; d) we have demonstrated the pathogenic nature of PF IgG4 autoantibodies and PF Fab' fragments in PF. e) We have characterized proteolytic fragments from human epidermis which react specifically with PF and PV autoantibodies. In Bullous Pemphigoid (BP) we have demonstrated that: f) BP autoantibodies recognize hemidesmosomal antigens. g) the sera of BP patients react with two "major" BP antigens (240 kD and 180 kD) nad other lower m.w. "minor" BP antigens; and h) herpes gestationis sera react with the 180 kD BP antigen. i) We have recently identified two cDNA clones from a keratinocyte cDNA library corresponding to the two major BP antigens (180 and 240 kD). Analyses of the cDNA-encoded fusion proteins showed that the 180 and 240 kD BP antigens are indeed distinct hemidesmosomal polypeptides. Sequence analysis has revealed that the 180 kD BP antigen contains a collagen-like domain which is a potential basement membrane binding site. Autoantibody- mediated disruption of such an interaction may be relevant to blister formation in BP patients. The present application includes studies designed to continue and advance the knowledge in immunopathogenesis of PV, PF and BP. This will be accomplished by defining at the molecular level: a) the epitopes recognized by the respective autoantibodies, b) the nature and relationship of the "minor" and "major" BP antigens, c) the IgG subclass of the IgG autoantibody systems present int he sera of these patients, d) the mechanisms by which Fab' from PV and PF autoantibodies cause acantholysis by impairing the adhesive function of its antigen), and e) by developing the animal model of BP based on the results of epitope mapping studies. We are confident that we have the expertise and the laboratory facilities to continue our success in advancing our understanding of the immunopathology of these diseases. The data generated will be novel and relevant.